Bisphosphonates were first developed to complex calcium in hard water to improve detergent performance. Bisphosphonates have since been found to be useful in the treatment and prevention of diseases or conditions characterized by abnormal calcium and phosphate metabolism. Such conditions may be divided into two broad categories:
1. Conditions which are characterized by anomalous mobilization of calcium and phosphate leading to general or specific bone loss or excessively high calcium and phosphate levels in the fluids of the body. Such conditions are sometimes referred to as pathological hard tissue demineralization.
2. Conditions which cause or result from deposition of calcium and phosphate anomalously in the body. These conditions are sometimes referred to as pathological calcifications.
The first category includes osteoporosis, a condition in which bone hard tissue is lost disproportionately to the development of new hard tissue ultimately resulting in fractures. Essential quantities of cancellous bone are lost, and marrow and bone spaces become larger, resulting in reduced cancellous bone strength. Bone also becomes less dense and fragile. Osteoporosis can be sub-classified as genetic, senile, drug induced (e.g., adrenocorticoid, as can occur in steroid therapy), disease induced (e.g., arthritic and tumor), etc., however the manifestations are similar. Another condition in the first category is Paget's disease (osteitis deformans). In this disease, dissolution of normal bone occurs, which is then haphazardly replaced by soft, poorly mineralized tissue such that the bone becomes deformed from pressures of weight bearing, particularly in the tibia and femur. Hyperparathyroidism, hypercalcemia of malignancy, arthritis, and osteolytic bone metastasis are conditions also included in the first category.
The second category, involving conditions manifested by anomalous calcium and phosphate deposition, includes myositis ossificans progressiva, calcinosis universalis, and such afflictions as arthritis, neuritis, bursitis, tendonitis, and other inflammatory conditions which predispose involved tissue to deposition of calcium phosphates.
A variety of polyphosphonic acid derivatives have been proposed for use in the treatment and prophylaxis of conditions involving abnormal calcium and phosphate metabolism. For example, diphosphonates, like ethane-1-hydroxy-1,1-diphosphonic acid (EHDP), propane-3-amino-1-hydroxy-1,1-diphosphonic acid (APD), and dichloromethane diphosphonic acid (Cl2MDP), have been the subject of considerable research efforts in this area. Paget's disease and heterotopic ossification have been treated with EHDP. Similarly, risedronate and alendronate have been used for treatment of bone disorders, U.S. Pat. No. 4,990,503 discloses heterocyclic bisphosphonic acid derivatives and their use as bone resorption inhibitors, and U.S. Pat. No. 7,745,422 teaches bisphosphonate derivatives for use in bone resorption and bone pain. However, these patents fail to teach bisphosphonate cyclic acetal compounds. U.S. Pat. No. 5,719,303 discloses bisphosphonic acid derivatives, and one bisphosphonic cyclic acetal, Example No. 471. This example, however, has a chemical structure unlike the bisphosphonate cyclic acetals disclosed herein and, in vivo, would not likely release an effective amount of the bisphosphonate.
However, bisphosphonates suffer from side effects and pharmacological disadvantages as orally administered agents. Some of the currently available bisphosphonates, e.g., alendronate, tiludronate, and risedronate, may cause esophageal irritation and ulceration. Therefore, it is recommended that the patients remain upright for 30 minutes after taking the medication. In addition, bisphosphonates usually have very low oral bioavailability: generally only 0.2% to 5% of an orally administered bisphosphonate is absorbed from the gastrointestinal tract. Bisphosphonates are usually very polar and can easily become negative charged, thus preventing absorption through paracellular transportation. They also have very low affinity to lipids, which makes it difficult for bisphosphonates to move across the cell membrane. Oral absorption is further reduced when taken with food, especially food rich in calcium. This “food effect” phenomenon can be explained by the formation of insoluble calcium salts of bisphosphonic acids which remain in the digestive tract without any detectable absorption. Bisphosphonic acids are known strong chelators of metal ions, including calcium, due to the presence of four acidic groups and a alpha-hydroxy substituent, when present. For example, with the calcium salts of alpha-hydroxybisphosphonic acids, the crystal structures show that the calcium ion is bound to two acidic hydroxyl groups from the different phosphate moieties and to the alpha-hydroxyl group. Therefore, there remains a need to develop bisphosphonates that maintain or enhance the pharmacological activity with fewer side effects and better absorption profiles.
Farnesyl pyrophosphate synthase (FPPS) is a key regulatory enzyme in the mevalonate pathway. This pathway, ubiquitous in mammalian cells, provides essential lipid molecules, such as cholesterol and isoprenoids, with isoprenoids being necessary for posttranslational prenylation of small GTPases. The blockage of this pathway is a concept that has found widespread clinical use, with statins as drugs that inhibit hydroxymethylglutaryl CoA reductase and reduce cholesterol biosynthesis, and nitrogen-containing bisphosphonates (N-BPs) as drugs for osteoporosis therapy that target FPPS and inhibit protein prenylation. In the case of N-BPs, the unique bone-targeting pharmacokinetic properties of these compounds cause selected inhibition of FPPS and loss of prenylated proteins in osteoclasts, thereby inhibiting the bone-destroying function of these cells.